Our overall objective is to study the biochemistry, physiology, and histopathology of the various diabetic, prediabetic, and obese stocks of mice available to us in order to establish the primary lesions involved in each of the phenotypically similar genetic obesities. The specific genes to be studied are diabetes (db), obese (ob), yellow (Ay), fat (fat), and tubby (tub). Each of these mutations produces severe obesity coupled with a varying degree of diabetes, depending on the inbred background in which the mutation is maintained. We propose to establish the nature of the metabolic changes in mutants that contribute to their thrifty, more efficient mechanisms of utilizing body stores and exogenous nutrients. We hope to establish whether a failure of thermogenesis in mutants spares sufficient energy to permit the excess weight gain observed when mutants are fed normal or even limited amounts of food. We also hope to establish the role of the increased rate of conversion of ketone bodies into lactate and glucose in mutants as a mechanism contributing to increased thriftiness. The advantages conferred on mutants by this increased metabolic efficiency will be evaluated with respect to the development and maintenance of diabetes in populations.